The Role of DNA Repair in Retroviral Infection The goal of this proposal is to examine two well-defined host DNA repair pathways that act as positive and negative regulators of retroviral infection. Our previous studies have identified the Nucleotide Excision Repair (NER) genes XPB(ERCC3) and XPD(ERCC2) as central players in a major retroviral cDNA degradation pathway that eliminates a substantial portion of the incoming cDNAs, and is responsible for significantly reducing the frequency of integration (negative retrovirus regulators). In more recent studies we have identified Base Excision Repair (BER) pathway genes that significantly enhance the efficiency of integration (positive retrovirus regulators). Both DNA repair pathways affect the retroviral life cycle at the relatively unexplored stages following reverse transcription and through completion of integration. We propose to examine the regulatory mechanisms of these two DNA repair pathways on retroviral infection with the following two specific aims: 1.) to define the components and mechanism of TFIIH mediated retroviral cDNA degradation pathway, and 2.) to elucidate the role of BER proteins on retroviral integration. These aims will be accomplished using experimental strategies that include both genetic and biochemical approaches. Understanding the mechanisms of these positive and negative regulators of retroviral infection may be the foundation for future anti-retroviral therapies. PUBLIC HEALTH RELEVANCE: Retroviruses, including HIV and the family of HTLV retroviruses, present a significant and continuing threat to public health. These studies aim at elucidating both an innate intracellular host defense against retroviral infection and a pathway of host proteins required for efficient retroviral infection. Both pathways appear to possess the potential to be exploited as targets for future novel anti-retroviral therapies.